Pharmacokinetics

Absorption

Distribution

Metabolism

Highly metabolized in the liver; CYP-450, including CYP3A4, may play a major role in oxidation and reduction of clonazepam.

Elimination

The half-life is 30 to 40 h. Less than 2% is excreted in the urine as unchanged drug.

Special Populations

Renal Function Impairment

Effects of renal disease on clonazepam pharmacokinetics have not been studied.

Hepatic Function Impairment

Effects of liver disease on clonazepam pharmacokinetics have not been studied.

Elderly

Controlled pharmacokinetic studies have not been conducted.

Children

Controlled pharmacokinetic studies have not been conducted.

Gender

Controlled pharmacokinetic studies have not been conducted.

Indications and Usage

For the treatment of Lennox-Gastaut syndrome, alone or as an adjunct; for the management of akinetic and myoclonic seizures and absence seizures unresponsive to succinimides; for the treatment of panic disorders with or without agoraphobia.

Contraindications

Dosage and Administration

Panic DisorderAdults

PO Start with 0.25 mg twice daily. An increase to the target dose for most patients of 1 mg/day may be made after 3 days. Dose may be increased in increments of 0.125 to 0.25 mg twice daily every 3 days until panic disorder is controlled or adverse effects make further increases undesired (max, 4 mg/day). When discontinuation is necessary, decrease dose gradually, with a decrease of 0.125 mg twice daily every 3 days until the drug is completely withdrawn.

Seizure DisordersAdults and Children older than 10 y or more than 30 kg

PO Do not exceed 1.5 mg/day in 3 divided doses initially. Increase by 0.5 to 1 mg every 3 days until seizures are adequately controlled or adverse effects make further increases undesirable (max, 20 mg/day).

Infants and Children 10 y and younger or 30 kg or less

PO 0.01 to 0.03 mg/kg/day in 2 to 3 divided doses (max, 0.05 mg/kg/day) initially. Increase by no more than 0.25 to 0.5 mg every 3 days until a maintenance dose of 0.1 to 0.2 mg/kg has been reached, unless seizures are controlled or adverse effects make further increases undesirable.

General Advice

To reduce the inconvenience of somnolence when treating patients with panic disorder, administration of 1 dose at bedtime may be desirable.

When treating seizure disorder, dosage should be divided into 3 equal doses whenever possible. If doses are not equally divided, give the largest dose at bedtime.

Do not open the carton containing orally disintegrating tablets until immediately before the dose is to be administered.

The orally disintegrating tablet disintegrates rapidly in saliva and may be swallowed with or without water.

May decrease the metabolism of clonazepam, thereby increasing the pharmacologic and toxic effects. Clonazepam dosage adjustment may be needed.

Clozapine

Ataxia, delirium, sedation, and sialorrhea may occur with coadministration. Severe orthostatic hypotension and respiratory depression may occur when clozapine is added to, or started with, clonazepam. Do not start agents simultaneously. The addition of clonazepam to an established clozapine regimen may carry less risk than adding clozapine to clonazepam. Careful clinical monitoring is advised, especially during the first 48 hours of coadministration.

May result in increased sleep duration and CNS depression. Coadministration is contraindicated.

Theophyllines

May antagonize sedative effects.

Valproic acid

Toxicity of clonazepam may be increased, while the therapeutic effects of both drugs may be reduced (increased seizure risk). Teratogenic effects of both agents during the first trimester may be enhanced.

Miscellaneous

Precautions

Monitor

Ensure that CBC with differential and liver enzymes are evaluated periodically in patients on prolonged therapy. Ensure that therapy is periodically reviewed to determine if it needs to be continued without change or if a dose change (eg, increase, decrease, discontinuation) is indicated. Monitor patients for emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pregnancy

Category D . Clonazepam is assumed to be capable of causing an increased risk of congenital abnormalities.

Lactation

Excreted in breast milk. Breast-feeding is not recommended.

Children

Panic disorder

Safety and efficacy not established.

Seizure disorders

Long-term use may cause adverse effects, such as delayed mental or physical development.

Elderly

Initiate with low doses and observe closely; confusion and oversedation may occur.

Renal Function

Use drug with caution to avoid accumulation.

Hepatic Function

Use drug with caution to avoid accumulation; contraindicated in patients with significant liver disease.

Hazardous Tasks

Dependence

Hypersalivation

Because an increase in salivation may occur, use with caution in patients who have difficulty handling secretions or those with chronic respiratory disease.

Seizure

In patients with multiple seizure types, clonazepam may increase incidence or precipitate onset of tonic-clonic seizures.

Suicidal behavior and ideation

Antiepileptic drugs increase the risk of suicidal thinking and behavior in patients taking these drugs for any indication.

Withdrawal

Abrupt discontinuation, particularly in patients on long-term, high-dose therapy, may precipitate status epilepticus. If treatment is to be discontinued or the dose reduced, gradually taper the dose and monitor patient for withdrawal symptoms.

Overdosage

Symptoms

Coma, confusion, diminished reflexes, somnolence.

Patient Information

Advise patients or caregivers to read the Medication Guide before starting therapy and with each refill.

Inform patients that, because benzodiazepines may produce psychological and physical dependence, it is advisable that they consult with their health care provider before either increasing the dose or abruptly discontinuing the drug.

Advise patients taking orally disintegrating tablets to peel back the foil on the blister, and, using dry hands, immediately remove the tablet and place in mouth. Advise patients that the tablet disintegrates rapidly in saliva and may be swallowed with or without water.

Advise patients that if medication needs to be discontinued, it will be slowly withdrawn unless safety concerns (eg, rash) require a more rapid withdrawal.

Instruct patients to avoid alcoholic beverages and other depressants while taking this medication.

Counsel patients, families, or caregivers that antiepileptic drugs may increase the risk of suicidal thoughts and behavior and to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm, and to immediately report any of these symptoms to their health care provider.

Advise patients that drug may cause drowsiness or impair judgment, thinking, or reflexes, and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.